1. Field of the Invention
The invention relates to targeted binding agents against the target antigen PDGFR-alpha and uses of such agents. In some embodiments, the invention relates to fully human monoclonal antibodies directed to PDGFR-alpha and uses of these antibodies. Aspects of the invention also relate to hybridomas or other cell lines expressing such targeted binding agents or antibodies. The described targeted binding agents and antibodies are useful as diagnostics and for the treatment of diseases associated with the activity and/or overexpression of PDGFR-alpha.
2. Description of the Related Art
Platelet derived growth factor (PDGF) is a protein that regulates cell growth and division. There are five different isoforms of PDGF (A, B, C, D, and an AB heterodimer) that exist as dimers and activate the cellular response through two different receptors (PDGFR-alpha and PDGFR-beta). Specifically, PDGF dimers bind to two receptors simultaneously to induce receptor dimerization, autophosphorylation and intracellular signaling.
Platelet derived growth factor receptor-alpha (PDGFR-alpha, also known as CD140a), is a type III receptor tyrosine kinase characterized by an extracellular domain having five IgG-like domains, a transmembrane domain and a catalytic intracellular domain. PDGFR-alpha can form homodimers or heterodimers with the structurally similar PDGFR-beta. PDGF-AA activates only alpha-alpha receptor dimers, PDGF-AB and PDGF-CC activate alpha-alpha and/or alpha-beta receptor dimers and PDGF-BB activates all three combinations of receptor dimers.
PDGFR-alpha has been linked to tumorigenesis and has been implicated in a number of cancers including breast, lung, ovarian, prostate, colon and endometrial cancers, as well as hepatocellular carcinoma, glioblastoma, melanoma, and gastrointestinal stromal tumor (GIST)).
Several companies have developed therapeutic agents that target PDGFR-alpha. Gleevec® (Novartis®) and SUTENT/SU11248 (sunitinib malate, Pfizer®) are small molecule drugs that target PDGFR-alpha as well as other receptor tyrosine kinases. In addition, monoclonal antibodies that target PDGFR-alpha have been reported. International publication number WO 1992/013867 describes that mouse or rabbit monoclonal and/or polyclonal antibodies may be prepared to PDGF receptor constructs. International publication number WO 1995/000659 relates to a monoclonal antibody, specific for PDGFR-alpha, characterized in that it binds PDGFR-alpha and does not bind PDGFR-beta. The application discloses two antibodies; characterized as having half maximal binding affinity of 50 pM and 75 pM as measured by solid phase enzyme linked immunosorbent assay. International publication number WO2006/138729 discloses a fully human monoclonal antibody, termed 3G3 (ImClone Systems, Inc.), that targets PDGFR-alpha. This antibody has a reported affinity for soluble PDGFR-alpha of 40 pM as measured in a bivalent affinity assay; in which soluble PDGFR-alpha was immobilized on a sensor chip and antibody was injected at various concentrations. As discussed herein, in a bivalent assay, experimental artifacts may affect the measured affinity.
An antibody with an affinity higher than 40 pM, may be desirable as such an antibody may produce a greater extent and/or duration of PDGFR-alpha inhibition when administered to humans at standard doses. An antibody with an affinity higher than 40 pM may be administered at a lower effective dose than an antibody with a lower affinity, or may be administered at longer dosing intervals in comparison with a standard dosing interval for an antibody with a lower affinity.